U.S. patent application number 10/738578 was filed with the patent office on 2004-11-04 for combinations of superoxide dismutase mimetics and opioids.
This patent application is currently assigned to MetaPhore Pharmaceuticals, Inc.. Invention is credited to Salvemini, Daniela.
Application Number | 20040219138 10/738578 |
Document ID | / |
Family ID | 27367740 |
Filed Date | 2004-11-04 |
United States Patent
Application |
20040219138 |
Kind Code |
A1 |
Salvemini, Daniela |
November 4, 2004 |
Combinations of superoxide dismutase mimetics and opioids
Abstract
Combinations of synthetic low molecular weight catalysts for the
dismutation of superoxide and opioids are potent analgesics that
are effective in elevating the pain threshold in hyperalgesic
conditions.
Inventors: |
Salvemini, Daniela;
(Chesterfield, MO) |
Correspondence
Address: |
SONNENSCHEIN NATH & ROSENTHAL LLP
P.O. BOX 061080
WACKER DRIVE STATION, SEARS TOWER
CHICAGO
IL
60606-1080
US
|
Assignee: |
MetaPhore Pharmaceuticals,
Inc.
Pharmacia Corporation
|
Family ID: |
27367740 |
Appl. No.: |
10/738578 |
Filed: |
December 16, 2003 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10738578 |
Dec 16, 2003 |
|
|
|
09997974 |
Nov 30, 2001 |
|
|
|
09997974 |
Nov 30, 2001 |
|
|
|
09634152 |
Aug 9, 2000 |
|
|
|
6395725 |
|
|
|
|
09634152 |
Aug 9, 2000 |
|
|
|
09057831 |
Apr 9, 1998 |
|
|
|
6180620 |
|
|
|
|
60050402 |
Jun 20, 1997 |
|
|
|
Current U.S.
Class: |
424/94.4 ;
514/184; 514/282 |
Current CPC
Class: |
C07F 13/005 20130101;
A61K 31/555 20130101 |
Class at
Publication: |
424/094.4 ;
514/184; 514/282 |
International
Class: |
A61K 038/44; A61K
031/555; A61K 031/485 |
Claims
What is claimed is:
1. A combination comprising: (a) at least one opioid; and (b) at
least one synthetic superoxide dismutase catalyst.
2. A combination according to claim 1, wherein the combination is
capable of treating, preventing, reversing or inhibiting pain or
inflammation when administered to a patient in need thereof.
3. A combination according to claim 2, wherein the combination is
capable of producing an additive or synergistic antihyperalgesia or
antinociception effect in the patient after administering the
combination.
4. A combination according to claim 3, wherein the opioid of the
combination comprises at least about 50% less than the same opioid
administered alone to achieve the antihyperalgesia or
antinociception effect.
5. A combination according to claim 4, wherein the opioid of the
combination comprises at least about 25% less than the same opioid
administered alone to achieve the antihyperalgesia or
antinociception effect.
6. A combination according to claim 5, wherein the opioid of the
combination comprises at least about 10% less than the same opioid
administered alone to achieve the antihyperalgesia or
antinociception effect.
7. A combination according to claim 6, wherein the opioid of the
combination comprises at least about 1% less than the same opioid
administered alone to achieve the antihyperalgesia or
antinociception effect.
8. A combination according to claim 2, wherein the opioid and the
synthetic superoxide dismutase catalyst are combined prior to
administration to the patient.
9. A combination according to claim 2, wherein the opioid and the
synthetic superoxide dismutase catalyst are combined upon
administration to the patient.
10. A combination according to claim 1, wherein the opioid is
selected from the group consisting of morphine, oxycontin,
oxycodone, codeine, fentanyl and any combination thereof.
11. A combination according to claim 1, wherein the synthetic
superoxide dismutase catalyst is represented by the formula:
25wherein (a) R, R', R.sub.1, R'.sub.1, R.sub.2, R'.sub.2, R.sub.3,
R'.sub.3, R.sub.4, R'.sub.4, R.sub.5, R'.sub.5, R.sub.6, R'.sub.6,
R.sub.7 R'.sub.7, R.sub.8, R'.sub.8, R.sub.9, and R'.sub.9
independently are selected from the group consisting of hydrogen
and substituted or unsubstituted alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl,
cycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl,
alkenylcycloalkyl, alkenylcycloalkenyl, heterocyclic, aryl and
aralkyl radicals; and (b) optionally, R.sub.1 or R'.sub.1 and
R.sub.2 or R'.sub.2, R.sub.3 or R'.sub.3 and R.sub.4 or R'.sub.4,
R.sub.5 or R'.sub.5 and R.sub.6 or R'.sub.6, R.sub.7 or R'.sub.7
and R.sub.8 or R'.sub.8, or R.sub.9 or R'.sub.9 and R or R'
together with the carbon atoms to which they are attached
independently form a substituted or unsubstituted, saturated,
partially saturated or unsaturated cyclic or heterocyclic having 3
to 20 carbon atoms; and (c) optionally, R or R' and R.sub.1 or
R'.sub.1, R.sub.2 or R'.sub.2 and R.sub.3 or R'.sub.3, R.sub.4 or
R'.sub.4 and R.sub.5 or R'.sub.5, R.sub.6 or R'.sub.6 and R.sub.7
or R'.sub.7, or R.sub.8 or R'.sub.8 and R.sub.9 or R'.sub.9
together with the carbon atoms to which they are attached
independently form a substituted or unsubstituted nitrogen
containing heterocycle having 2 to 20 carbon atoms, which may be an
aromatic heterocycle wherein the hydrogen attached to the nitrogen
which is both part of the heterocycle and the macrocycle and the R
groups attached to the carbon atoms which are both part of the
heterocycle and the macrocycle are absent; and (d) optionally, R
and R', R.sub.1 and R'.sub.1, R.sub.2 and R'.sub.2, R.sub.3 and
R'.sub.3, R.sub.4 and R'.sub.4, R.sub.5 and R'.sub.5, R.sub.6 and
R'.sub.6, R.sub.7 and R'.sub.7, R.sub.8 and R'.sub.8, and R.sub.9
and R'.sub.9, together with the carbon atom to which they are
attached independently form a substituted or unsubstituted,
saturated, partially saturated, or unsaturated cyclic or
heterocyclic having 3 to 20 carbon atoms; and (e) optionally, one
of R, R', R.sub.1, R'.sub.1, R.sub.2, R'.sub.2, R.sub.3, R'.sub.3,
R.sub.4, R'.sub.4, R.sub.5, R'.sub.5, R.sub.6, R'.sub.6, R.sub.7,
R'.sub.7, R.sub.8, R'.sub.8, R.sub.9, and R'.sub.9 together with a
different one of R, R', R.sub.1, R'.sub.1, R.sub.2, R'.sub.2,
R.sub.3, R'.sub.3, R.sub.4, R'.sub.4, R.sub.5, R'.sub.5, R.sub.6,
R'.sub.6, R.sub.7, R'.sub.7, R.sub.8, R'.sub.8, R.sub.9, and
R'.sub.9, attached to a different carbon atom in the macrocycle are
bound to form a strap represented by the
formula:--(CH.sub.2).sub.x--M--(CH.sub.2).sub.w--L--(CH.sub.2).sub.z--J---
(CH.sub.2).sub.y--wherein w, x, y and z independently are integers
from 0 to 10 and M, L and J are independently selected from the
group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, oxa,
thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl,
phosphino, phosphonium, keto, ester, alcohol, carbamate, urea,
thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and
combinations thereof; and (f) combinations of any of (a) through
(e) above; and wherein M is selected from the group consisting of
copper, manganese and zinc; X, Y and Z are pharmaceutically
acceptable counter ions, or together are a pharmaceutically
acceptable polydentate ligand; and n is an integer from 0 to 3.
12. A combination according to claim 11, wherein the synthetic
superoxide dismutase catalyst is represented by the formula: 26
13. A combination according to claim 11, wherein the synthetic
superoxide dismutase catalyst is represented by the formula: 27
14. A combination according to claim 11, wherein the synthetic
superoxide dismutase catalyst is represented by the formula: 28
15. A compound of the formula A.sub.n-Q.sub.m, wherein A is a
superoxide dismutase catalyst moiety, Q is an opioid moiety, and n
and m are independently integers from 1 to 3.
16. A compound according to claim 15, wherein the opioid moiety is
selected from the group consisting of morphine, oxycontin,
oxycodone, codeine, fentanyl and any combination thereof.
17. A compound according to claim 15, wherein the synthetic
superoxide dismutase catalyst moiety is represented by the formula:
29wherein (a) R, R', R.sub.1, R'.sub.1, R.sub.2, R'.sub.2, R.sub.3,
R'.sub.3, R.sub.4, R'.sub.4, R.sub.5, R'.sub.5, R.sub.6, R'.sub.6,
R.sub.7, R'.sub.7, R.sub.8, R'.sub.8, R.sub.9, and R'.sub.9
independently are selected from the group consisting of hydrogen
and substituted or unsubstituted alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl,
cycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl,
alkenylcycloalkyl, alkenylcycloalkenyl, heterocyclic, aryl and
aralkyl radicals; and (b) optionally, R.sub.1 or R'.sub.1, and
R.sub.2 or R'.sub.2, R.sub.3 or R'.sub.3 and R.sub.4 or R'.sub.4,
R.sub.5 or R'.sub.5 and R.sub.6 or R'.sub.6, R.sub.7 or R' .sub.7
and R.sub.8 or R'.sub.8, or R.sub.9 or R'.sub.9 and R or R'
together with the carbon atoms to which they are attached
independently form a substituted or unsubstituted, saturated,
partially saturated or unsaturated cyclic or heterocyclic having 3
to 20 carbon atoms; and (c) optionally, R or R' and R.sub.1 or
R'.sub.1, R.sub.2 or R'.sub.2 and R.sub.3 or R'.sub.3, R.sub.4 or
R'.sub.4 and R.sub.5 or R'.sub.5, R.sub.6 or R'.sub.6 and R.sub.7
or R'.sub.7, or R.sub.8 or R'.sub.8 and R.sub.9 or R'.sub.9
together with the carbon atoms to which they are attached
independently form a substituted or unsubstituted nitrogen
containing heterocycle having 2 to 20 carbon atoms, which may be an
aromatic heterocycle wherein the hydrogen attached to the nitrogen
which is both part of the heterocycle and the macrocycle and the R
groups attached to the carbon atoms which are both part of the
heterocycle and the macrocycle are absent; and (d) optionally, R
and R', R.sub.1 and R'.sub.1, R.sub.2 and R'.sub.2, R.sub.3 and
R'.sub.3, R.sub.4 and R'.sub.4, R.sub.5 and R'.sub.5, R.sub.6 and
R'.sub.6, R.sub.7 and R'.sub.7, R.sub.8 and R'.sub.8, and R.sub.9
and R'.sub.9, together with the carbon atom to which they are
attached independently form a substituted or unsubstituted,
saturated, partially saturated, or unsaturated cyclic or
heterocyclic having 3 to 20 carbon atoms; and (e) optionally, one
of R, R', R.sub.1, R'.sub.1, R.sub.2, R'.sub.2, R.sub.3, R'.sub.3,
R.sub.4, R'.sub.4, R.sub.5, R'.sub.5, R.sub.6, R'.sub.6, R.sub.7,
R'.sub.7, R.sub.8, R'.sub.8, R.sub.9, and R'.sub.9 together with a
different one of R, R', R.sub.1, R'.sub.1, R.sub.2, R'.sub.2,
R.sub.3, R'.sub.3, R.sub.4, R'.sub.4, R.sub.5, R'.sub.5, R.sub.6,
R'.sub.6, R.sub.7, R'.sub.7, R.sub.8, R'.sub.8, R.sub.9, and
R'.sub.9 attached to a different carbon atom in the macrocycle are
bound to form a strap represented by the
formula:--(CH.sub.2).sub.x--M--(CH.sub.2).sub.w--L--(CH.sub.2).sub.z--J---
(CH.sub.2).sub.y--wherein w, x, y and z independently are integers
from 0 to 10 and M, L and J are independently selected from the
group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, oxa,
thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl,
phosphino, phosphonium, keto, ester, alcohol, carbamate, urea,
thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and
combinations thereof; and (f) combinations of any of (a) through
(e) above; and wherein M is selected from the group consisting of
copper, manganese and zinc; X, Y and Z are pharmaceutically
acceptable counter ions, or together are a pharmaceutically
acceptable polydentate ligand; and n is an integer from 0 to 3.
18. A compound according to claim 17, wherein the synthetic
superoxide dismutase catalyst is represented by the formula: 30
19. A compound according to claim 17, wherein the synthetic
superoxide dismutase catalyst is represented by the formula: 31
20. A compound according to claim 17, wherein the synthetic
superoxide dismutase catalyst is represented by the formula: 32
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending U.S.
application Ser. No. 09/997,974 filed Nov. 30, 2001 which is a
continuation-in-part of U.S. application Ser. No. 09/634,152 filed
Aug. 9, 2000, now U.S. Pat. No. 6,395,725, which is a divisional of
U.S. application Ser. No. 09/057,831 filed April 9,1998, now U.S.
Pat. No. 6,180,620, which claimed the benefit of U.S. Provisional
Application No. 60/050,402 filed Jun. 20, 1997. Each patent and
patent application above is incorporated herein by reference in its
entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable.
REFERENCE TO A SEQUENCE LISTING
[0003] Not Applicable.
BACKGROUND OF THE INVENTION
[0004] 1. Field of the Invention
[0005] The present invention relates to the treatment of humans and
lower animals in pain management: to prevent or relieve pain, to
prevent or reverse tolerance to opioid analgesics and hyperalgesia
associated with prolonged opioid treatment, and to prevent or
reduce symptoms of opioid withdrawal and related withdrawal
syndromes.
[0006] 2. Description of the Related Art
[0007] Numerous analgesics are known to medical science. Many
analgesics fall into one of two large categories--nonsteroidal
analgesic/anti-inflammatory drugs (NSAIDs) and opioids. NSAIDs
operate by inhibiting cyclooxygenase enzymes (including
cyclooxygenase-1 and cyclooxygenase-2, also known as COX-1 and
COX-2 respectively) and thereby the synthesis of prostaglandins.
Prostaglandins sensitize pain receptors, lowering the pain
threshold and making normal stimuli, such as touch and stretch
sensations, painful. NSAIDs can be quite effective at returning the
lowered pain threshold to normal but do not elevate the pain
threshold. Common NSAIDs available over-the-counter include:
ibuprofen (Advil.RTM.), naproxen (Aleve.RTM. or Naprosyn.RTM.)),
and aspirin (Bayer.RTM.). Prescription NSAIDs include:
celecoxib--Celebrex(.RTM., diclofenac--Voltaren.RTM.,
etodolac--Lodine.RTM., fenoprofen--Nalfon.RTM.- ,
indomethacin--Indocin.RTM., ketoprofen--Orudis.RTM., Oruvail.RTM.,
ketoralac--Toradol.RTM., oxaprozin--Daypro.RTM.,
nabumetone--Relafen.RTM.- , sulindac--Clinoril.RTM.,
tolmetin--Tolectin.RTM., and rofecoxib--Vioxx.RTM.).
[0008] A second class of pain relievers, opioids, operate by
mimicking natural peptides such as enkephalins and endorphins to
stimulate one or more of the .mu.-, .delta.- and .kappa.-receptor
systems in the nervous system. Opioids elevate the pain threshold
so that normally painful stimuli are perceived as less painful or
even euphoric. Opioids are commonly used in the clinical management
of severe pain, including chronic severe pain of the kind
experienced by cancer patients. Common opioids include morphine,
oxycontin, oxycodone, codeine and fentanyl.
[0009] Capsaicin and its derivatives operate by depleting local
stores of substance P, a neuropeptide involved in the transmission
of pain impulses and are used in several OTC analgesic
products.
[0010] Each of these classes of compounds has inherent problems and
limitations. The opioid analgesics are antagonized by analogous
N-allyl compounds such as naloxone; the NSAID analgesics are not.
NSAIDs that are nonselective for the cyclooxygenase-2 produced in
inflammation (COX-2) also inhibit constitutive cyclooxygenase-1
(COX-1), causing undesirable damage to the gastric mucosa. They
have limited effectiveness as analgesics in lowering an elevated
threshold to normal and are generally used for mild to moderate
pain. They are also ineffective drugs for elevation of the pain
threshold above normal levels, which prevents their use in pain
such as surgical pain where an underlying pathological condition
has not elevated the pain threshold.
[0011] Opioids have problems with tolerance and dependency, so that
over a course of therapy increasing dosages of compound are
required to achieve the same level of analgesia, and cessation of
opioid administration when analgesia is no longer needed elicits a
withdrawal syndrome with unpleasant and potentially serious
symptoms. The dependency and withdrawal syndrome both make it
difficult for the clinician to discontinue opioid therapy even when
the opioids are no longer effective in relieving pain because of
the development of tolerance. Narcotic induced hyperalgesia (NIH)
can also develop in association with tolerance to the opioids. All
of these factors limit the usefulness of opioids in the management
of chronic severe pain, despite their potency.
[0012] No adequate strategy has been devised to overcome the
development of opioid tolerance and provide an ongoing approach to
the management of chronic severe pain. Mechanisms of tolerance are
not well understood but are known to involve the NMDA receptor,
since the NMDA receptor antagonist MK-801 has been shown in rats to
prevent morphine tolerance. NMDA stimulates nitric oxide synthase
(NOS) and NOS has been observed histochemically in tissues that
contain opioid receptors and are important in the pain response,
such as the amygdala, cortical gray matter, and the substantia
gelatinosa of the spinal cord. Non-selective NOS inhibitors such as
NG-nitroarginine prevent and reverse morphine tolerance. However,
nonselective inhibition of NOS is associated with a vast array of
undesirable side effects, including hypertension, increased
platelet and white blood cell reactivity, decreased cerebral blood
flow, and gastrointestinal and renal toxicity.
[0013] Capsaicin and some of its derivatives, in addition to
producing analgesia, also elicit a burning sensation. This effect
is responsible for the pungency of hot peppers (Capscum spp.) and
limits the applicability of many members of this series of
compounds.
[0014] For these and other reasons, a continuing need exists for
new high potency analgesics which do not result in the drawbacks
listed above. A need also exists for methods for reversing
tolerance to opioid analgesics so that patients who require these
drugs for pain over extended periods can do so without loss of
potency and efficacy.
BRIEF SUMMARY OF THE INVENTION
[0015] Accordingly, it is an object of the invention to overcome
these and other problems associated with the related art. These and
other objects, features and technical advantages are achieved by
providing combinations of opioids and synthetic superoxide
dismutase catalysts for treating, preventing, reversing or
inhibiting pain or inflammation when administered to a patient in
need thereof.
[0016] This invention provides a combination of compositions
comprising (a) at least one opioid; and (b) at least one synthetic
superoxide dismutase catalyst. In one aspect, the combination is
capable of treating, preventing, reversing or inhibiting pain or
inflammation when administered to a patient in need thereof. In one
embodiment, the combination is capable of producing an additive or
synergistic antihyperalgesia or antinociception effect in the
patient after administering the combination.
[0017] Preferably, the opioid of the combination comprises at least
about 50% less than the same opioid administered alone to achieve
the antihyperalgesia or antinociception effect. More preferably,
the opioid of the combination comprises at least about 25% less
than the same opioid administered alone to achieve the
antihyperalgesia or antinociception effect. Still more preferably,
the opioid of the combination comprises at least about 10% less
than the same opioid administered alone to achieve the
antihyperalgesia or antinociception effect. And still more
preferably, the opioid of the combination comprises at least about
1% less than the same opioid administered alone to achieve the
antihyperalgesia or antinociception effect.
[0018] In accordance with one aspect of the invention, the opioid
and the synthetic superoxide dismutase catalyst are combined prior
to administration to the patient. In another aspect, the opioid and
the synthetic superoxide dismutase catalyst are combined upon
administration to the patient.
[0019] Preferably, the opioid is selected from the group consisting
of morphine, oxycontin, oxycodone, codeine, fentanyl and any
combination thereof. In accordance with another aspect of the
invention, the synthetic superoxide dismutase catalyst is
represented by the formula: 1
[0020] wherein (a) R, R', R.sub.1, R'.sub.1, R.sub.2, R'.sub.2,
R.sub.3, R'.sub.3, R.sub.4, R'.sub.4, R.sub.5, R'.sub.5, R.sub.6,
R'.sub.6, R.sub.7, R'.sub.7, R.sub.8, R'.sub.8, R.sub.9, and
R'.sub.9 independently are selected from the group consisting of
hydrogen and substituted or unsubstituted alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl,
cycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl,
alkenylcycloalkyl, alkenylcycloalkenyl, heterocyclic, aryl and
aralkyl radicals; and (b) optionally, R.sub.1 or R'.sub.1 and
R.sub.2 or R'.sub.2, R.sub.3 or R'.sub.3 and R.sub.4 or R'.sub.4,
R.sub.5 or R'.sub.5 and R.sub.6 or R'.sub.6, R.sub.7 or R'.sub.7,
and R.sub.8, or R'.sub.8, or R.sub.9 or R'.sub.9 and R or R'
together with the carbon atoms to which they are attached
independently form a substituted or unsubstituted, saturated,
partially saturated or unsaturated cyclic or heterocyclic having 3
to 20 carbon atoms; and (c) optionally, R or R' and R.sub.1 or
R'.sub.1, R.sub.2 or R'.sub.2 and R.sub.3 or R'.sub.3, R.sub.4 or
R'.sub.4 and R.sub.5 or R'.sub.5, R.sub.6 or R'.sub.6 and R.sub.7
or R'.sub.7, or R.sub.8 or R'.sub.8 and R.sub.9 or R'.sub.9
together with the carbon atoms to which they are attached
independently form a substituted or unsubstituted nitrogen
containing heterocycle having 2 to 20 carbon atoms, which may be an
aromatic heterocycle wherein the hydrogen attached to the nitrogen
which is both part of the heterocycle and the macrocycle and the R
groups attached to the carbon atoms which are both part of the
heterocycle and the macrocycle are absent; and (d) optionally, R
and R', R.sub.1 and R'.sub.1, R.sub.2 and R'.sub.2, R.sub.3 and
R'.sub.3, R.sub.4 and R'.sub.4, R.sub.5 and R'.sub.5, R.sub.6 and
R'.sub.6, R.sub.7, and R'.sub.7, R.sub.8, and R'.sub.8, and R.sub.9
and R'.sub.9, together with the carbon atom to which they are
attached independently form a substituted or unsubstituted,
saturated, partially saturated, or unsaturated cyclic or
heterocyclic having 3 to 20 carbon atoms; and (e) optionally, one
of R, R', R.sub.1, R'.sub.1, R.sub.2, R'.sub.2, R.sub.3, R'.sub.3,
R.sub.4, R'.sub.4, R.sub.5, R'.sub.5, R.sub.6, R'.sub.6, R.sub.7,
R'.sub.7, R.sub.7, R.sub.8, R'.sub.8, R.sub.9, and R'.sub.9
together with a different one of R, R', R.sub.1, R'.sub.1, R.sub.2,
R'.sub.2, R.sub.3, R'.sub.3, R.sub.4, R'.sub.4, R.sub.5, R'.sub.5,
R.sub.6, R'.sub.6, R.sub.7, R'.sub.7, R.sub.8, R'.sub.8, R.sub.9,
and R'.sub.9attached to a different carbon atom in the macrocycle
are bound to form a strap represented by the formula:
--(CH.sub.2).sub.x--M--(CH.sub.2).sub.w--L--(CH.sub.2).sub.z--J--(CH.sub.2-
).sub.y--
[0021] wherein w, x, y and z independently are integers from 0 to
10 and M, L and J are independently selected from the group
consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, oxa,
thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl,
phosphino, phosphonium, keto, ester, alcohol, carbamate, urea,
thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and
combinations thereof; and (f) combinations of any of (a) through
(e) above; and wherein M is selected from the group consisting of
copper, manganese and zinc; X, Y and Z are pharmaceutically
acceptable counter ions, or together are a pharmaceutically
acceptable polydentate ligand; and n is an integer from 0 to 3.
[0022] Preferably, the synthetic superoxide dismutase catalyst is
represented by the formula: 2
[0023] This invention provides a compound of the formula
A.sub.n-Q.sub.m, wherein A is a superoxide dismutase catalyst
moiety, Q is an opioid moiety, and n and m are independently
integers from 1 to 3. Preferably, the opioid is selected from the
group consisting of morphine, oxycontin, oxycodone, codeine,
fentanyl and any combination thereof. In accordance with one aspect
of the invention, the synthetic superoxide dismutase catalyst
moiety is represented by the formula: 3
[0024] wherein (a) R, R', R.sub.1, R'.sub.1, R.sub.2, R'.sub.2,
R.sub.3, R'.sub.3, R.sub.4, R'.sub.4, R.sub.5, R'.sub.5, R.sub.6,
R'.sub.6, R.sub.7, R'.sub.7, R.sub.8, R'.sub.8, R.sub.9, and
R'.sub.9, independently are selected from the group consisting of
hydrogen and substituted or unsubstituted alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl,
cycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl,
alkenylcycloalkyl, alkenylcycloalkenyl, heterocyclic, aryl and
aralkyl radicals; and (b) optionally, R.sub.1 or R'.sub.1 and
R.sub.2 or R'.sub.2, R.sub.3 or R'.sub.3 and R.sub.4 or R'.sub.4,
R.sub.5 or R'.sub.5 and R.sub.6 or R'.sub.6, R.sub.7 or R'.sub.7
and R.sub.8 or R'.sub.8, or R.sub.9 or R'.sub.9 and R or R'
together with the carbon atoms to which they are attached
independently form a substituted or unsubstituted, saturated,
partially saturated or unsaturated cyclic or heterocyclic having 3
to 20 carbon atoms; and (c) optionally, R or R'and R.sub.1 or
R'.sub.1, R.sub.2 or R'.sub.2 and R.sub.3 or R'.sub.3, R.sub.4 or
R'.sub.4 and R.sub.5 or R'.sub.5, R.sub.6 or R'.sub.6 and R.sub.7
or R'.sub.7, or R.sub.8 or R'.sub.8 and R.sub.9 or R'.sub.9
together with the carbon atoms to which they are attached
independently form a substituted or unsubstituted nitrogen
containing heterocycle having 2 to 20 carbon atoms, which may be an
aromatic heterocycle wherein the hydrogen attached to the nitrogen
which is both part of the heterocycle and the macrocycle and the R
groups attached to the carbon atoms which are both part of the
heterocycle and the macrocycle are absent; and (d) optionally, R
and R', R.sub.1 and R'.sub.1, R.sub.2 and R'.sub.2, R.sub.3 and
R'.sub.3, R.sub.4 and R'.sub.4, R.sub.5 and R'.sub.5, R.sub.6 and
R'.sub.6, R.sub.7, R.sub.8 and R'.sub.8, and R.sub.9 and R'.sub.9,
together with the carbon atom to which they are attached
independently form a substituted or unsubstituted, saturated,
partially saturated, or unsaturated cyclic or heterocyclic having 3
to 20 carbon atoms; and (e) optionally, one of R, R', R.sub.1,
R'.sub.1, R.sub.2, R'.sub.2, R.sub.3, R'.sub.3, R.sub.4, R'.sub.4,
R.sub.5, R'.sub.5, R.sub.6, R'.sub.6, R.sub.7, R'.sub.7, R.sub.8,
R'.sub.8, R.sub.9, and R'.sub.9 together with a different one of R,
R', R.sub.1, R'.sub.1, R.sub.2, R'.sub.2, R.sub.3, R'.sub.3,
R.sub.4, R'.sub.4, R.sub.5, R'.sub.5, R.sub.6, R'.sub.6, R.sub.7,
R'.sub.7R.sub.8, R'.sub.8, R.sub.9, and R'.sub.9 attached to a
different carbon atom in the macrocycle are bound to form a strap
represented by the formula:
--(CH.sub.2).sub.x--M--(CH.sub.2).sub.w--L--(CH.sub.2).sub.z--J--(CH.sub.2-
).sub.y--
[0025] wherein w, x, y and z independently are integers from 0 to
10 and M, L and J are independently selected from the group
consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, oxa,
thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl,
phosphino, phosphonium, keto, ester, alcohol, carbamate, urea,
thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and
combinations thereof; and (f) combinations of any of (a) through
(e) above; and wherein M is selected from the group consisting of
copper, manganese and zinc; X, Y and Z are pharmaceutically
acceptable counter ions, or together are a pharmaceutically
acceptable polydentate ligand; and n is an integer from 0 to 3.
[0026] Preferably, the synthetic superoxide dismutase catalyst is
represented by the formula: 4
[0027] These and other features, aspects and advantages of the
present invention will become better understood with reference to
the following description, examples and appended claims.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0028] FIG. 1 is a graph depicting the results of a study on the
inhibition of carrageenan-induced hyperalgesia by intravenously
injected SC-72325. The drug was given at 3 hours post carrageenan
injection.
[0029] FIGS. 2 and 3 are graphs depicting the results of a study on
inhibition of carrageenan-induced hyperalgesia by intramuscular
injection of either SOD mimic compound SC-72325 (Example 157) or
the nonsteroidal anti-inflammatory drug ketorolac.
[0030] FIG. 4 is a graph depicting the results of a study comparing
the effects of SC-72325 versus ketorolac on carrageenan-induced
increase of PGE-2 in cerebrospinal fluid.
[0031] FIG. 5 is a graph depicting the results of a study comparing
the effects of SC-72325 versus ketorolac on carrageenan-induced
release of PGE-2 in paw exudate.
[0032] FIG. 6 is a graph depicting the results of a study on
inhibition of formalin-induced nociception by subcutaneous
injection of SC-72325A.
[0033] FIG. 7 is a graph depicting the results of a study on
inhibition of carrageenan-induced hyperalgesia by subcutaneous
injection of SC-72325A. The drug was given at three (3) hours post
carrageenan.
[0034] FIG. 8 is a graph depicting the results of a study on
inhibition of carrageenan-induced hyperalgesia by subcutaneous
injection of SC-72325A and morphine-SC-72325A synergistic
effect.
[0035] FIG. 9 is a graph depicting the results of a study on
carrageenan-induced hyperalgesia by SC-72325A and ketorolac. Drugs
given by subcutaneous injection at three (3) hours post
carrageenan.
[0036] FIG. 10 is a graph depicting the results of a study on the
time-related and dose-dependent antihyperalgesia effect of
SC-72325A over the dose range of 0.3 to 30 mg/kg in the SNL
(L.sub.5/L.sub.6) model. Drugs administered via subcutaneous
injection.
[0037] FIG. 11 is a graph depicting the results of a study on the
time-related and dose-dependent attenuation of cold allodynia of
SC-72325A over the dose range of 1 to 10 mg/kg.
DETAILED DESCRIPTION OF THE INVENTION
[0038] This invention is based upon surprising discoveries
involving certain organometallic complexes designed as synthetic
catalysts for use in the body. These catalysts have been designed
as synthetic replacements for or adjuncts to the naturally
occurring enzyme superoxide dismutase (SOD).
[0039] Naturally occurring SOD scavenges and eliminates the
toxicity of free superoxide radicals (O.sub.2.sup..cndot.-)
liberated by certain metabolic reactions. Although these free
radicals play a major (and deleterious) role in the inflammatory
response and other toxic reactions to injury, neither superoxide
nor SOD has been known to be directly involved in pain perception.
In addition, SOD has a very short biological half-life, on the
order of seconds or minutes rather than hours, so it would be
considered unsuitable for treatment of conditions in which
increased dismutation of superoxide radicals would be desirable
over periods of from minutes to days.
[0040] Dismutation of superoxide radicals is catalyzed by a
coordinated transition metal ion. In the natural SOD enzyme, the
metal is manganese, copper or zinc and the coordination complex is
a conventional protein structure. Synthetic SOD catalysts also use
transition metals, complexed with low molecular weight organic
ligands, generally polydentate N-containing macrocycles. These
molecules have been designed to be highly efficient and to overcome
the pharmacokinetic disadvantages of natural SOD enzyme. The
k.sub.cat of some of these compounds is as high as about 10.sup.9
(see Example 165), indicating extraordinary catalytic efficiency,
as effective as the natural enzyme and approaching the theoretical
rate at which diffusion can deliver free radical substrate to the
catalyst under biological conditions. They also have oil:water
partition coefficients (.sub.log P) that provide excellent
bioavailability, and stability in the body on the order of hours to
days. Their small size and low molecular weight makes it possible
for the synthetic catalysts to cross membrane barriers that
restrict movement of natural SOD, and their non-protein structure
reduces the risk of allergic reactions that have been a problem
with the administration of protein-based recombinant SOD. Finally,
natural SOD produces hydrogen peroxide in the process of
dismutating superoxide, yet hydrogen peroxide inhibits natural SOD,
effectively self-limiting the efficacy of the natural compound. In
contrast, synthetic small-molecule SOD catalysts are not
susceptible to the action of hydrogen peroxide and thus retain
their effectiveness.
[0041] Synthetic SOD catalysts have been proposed in the past for
the treatment and prevention of inflammation, ischemia-reperfusion
injury, and similar conditions where tissue damage is mediated by
levels of free superoxide radicals that overwhelm natural SOD, but
they have not been proposed for use as analgesics in the treatment
of pain.
[0042] It has now been discovered that synthetic SOD catalysts are
highly effective as analgesics to prevent or provide relief from
pain in conditions in which the pain threshold is elevated. It has
also been discovered that these same compounds are effective in
preventing or reversing tolerance to opioid analgesics, that are
used to elevate the pain threshold above normal levels.
[0043] No known mechanism accounts for the analgesic properties of
these compounds. However, the data shown in the examples illustrate
that these compounds can be as effective as morphine in preventing
and relieving certain kinds of pain. Y. Lin et al., Int. J.
Maxillofac. Surg. 23:428429 (1994) reported the use of
intra-articular injections of human Cu/Zn superoxide dismutase as a
nonsteroidal anti-inflammatory in the treatment of
temporomandibular joint dysfunction. Positive response in terms of
mandibular movement and pain was observed in 83% of patients. The
authors note that the results "are remarkable because SOD has been
studied and shown to exert no peripheral or central analgesic
effect." They attribute the reduction in pain to the reduction in
tissue injury and inflammation associated with TMJ dysfunction.
[0044] Similarly, no known mechanism accounts for the ability of
these compounds to prevent or reverse tolerance to opioids. G. I.
Elmer et al., Euro. J. Pharmacol. 283 (1995) 227-232, reported that
transgenic mice expressing the human Cu/Zn superoxide dismutase
gene had an increase in .mu.-opioid receptor concentration in
dopaminergic related tissues and the central grey area of the CNS,
which was associated with a dose-related increased sensitivity to
.mu.-receptor agonists such as morphine. At the same time the
authors also observed conflicting effects of transgenic SOD on
.delta.-receptor agonists (mice heterozygous for the transgene were
more sensitive than homozygotes, which were more sensitive than
untransformed mice) and observed no effect of transgenic SOD on
.kappa.-receptor agonists.
[0045] Superoxide dismutase activity is known to play a critical
role in regulating the redox state of the cell, as reported by J.
L. Cadet, Int. J. Neurosci. 40, 13 (1988). This in turn is reported
by Marzullo and Hine, Science 208,1171 (1980) to significantly
affect in vitro .mu.-and .delta.-opioid binding.
[0046] In particular, this invention provides a method of producing
analgesia in a human or lower mammal patient, comprising
administering to the patient an analgesic amount of a functional
synthetic catalyst for the dismutation of superoxide radicals.
Based on the data obtained, it is reasonable to expect that any
superoxide dismutase catalyst will be effective in the practice of
this invention. A preferred synthetic catalyst is a coordination
complex of transition metal with an organic ligand. Preferred
transition metals are copper, manganese and zinc. Manganese is most
preferred. In general, the organic ligand is a N-containing
macrocycle, and most preferred ligands are selected from the group
consisting of compounds of the formula 5
[0047] wherein R, R', R.sub.1, R'.sub.1, R.sub.2, R'.sub.2,
R.sub.3, R'.sub.3, R.sub.4, R'.sub.4, R'.sub.5, R.sub.6, R'.sub.6,
R.sub.7, R'.sub.7, R.sub.8, R'.sub.8, R.sub.9 and R'.sub.9
independently are selected from the group consisting of hydrogen
and substituted or unsubstituted alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl,
alkylcycloalkyl, cycloalkenylalkyl, alkenylcycloalkyl,
alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and
aralkyl radicals, or R or R' and R.sub.1 or R'.sub.1, R.sub.2 or
R'.sub.2 and R.sub.3 or R'.sub.3, R.sub.4 or R'.sub.4 and R.sub.5
or R'.sub.5, R.sub.6 or R'.sub.6 and R.sub.7 or R'.sub.7, and
R.sub.8 or R'.sub.8 and R.sub.9 or R'.sub.9, together with the
carbon atoms to which they are attached independently form a
substituted or unsubstituted saturated, partially saturated or
unsaturated cyclic ring structure having 3 to 20 carbon atoms; or R
or R', R.sub.1 or R'.sub.1, and R.sub.2 or R'.sub.2, R.sub.3 or
R'.sub.3 and R.sub.4 or R'.sub.4, R.sub.5 or R'.sub.5 and R.sub.6
or R'.sub.6, R.sub.7 or R'.sub.7, and R.sub.8 or R'.sub.8, and
R.sub.9 or R'.sub.9, together with the carbon atoms to which they
are attached independently form a substituted or unsubstituted
nitrogen-containing heterocycle having 2 to 20 carbon atoms
provided that when the nitrogen containing heterocycle is an
aromatic heterocycle that does not have a hydrogen attached to the
nitrogen, the hydrogen attached to the nitrogen in the macrocycle
and the R groups attached to the same carbon atoms of the
macrocycle are absent; R and R', R.sub.1 and R'.sub.1, R.sub.2 and
R'.sub.2, R.sub.3 and R'.sub.3, R.sub.4 and R'.sub.4, R.sub.5 and
R'.sub.5, R.sub.6 and R'.sub.6, R.sub.7 and R'.sub.7, R.sub.8 and
R'.sub.8 and R'.sub.8 and R.sub.9 and R'.sub.9, together with the
carbon atom to which they are attached independently form a
substituted or unsubstituted saturated, partially saturated or
unsaturated ring structure having 3 to 20 carbon atoms; or two of
R, R', R.sub.1, R'.sub.1, R.sub.2, R'.sub.2, R.sub.3, R'.sub.3,
R.sub.4, R'.sub.4, R.sub.5, R'.sub.5, R.sub.6, R'.sub.6, R.sub.7,
R'.sub.7, R.sub.8, R'.sub.8, R.sub.9, and R'.sub.9 attached to
different carbon atoms of the macrocycle are bound to form a strap
structure of the formula
--(CH.sub.2).sub.x--M--(CH.sub.2).sub.w--L--(CH.sub.2).sub.z--J--(CH.sub.2-
).sub.y--
[0048] wherein w, x, y and z independently are integers from 0 to
10 and M, L and J are independently selected from the group
consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
heteroaryl, alkaryl, alkheteroaryl, aza, amido, ammonium, thio,
sulfonyl, sulfinyl, sulfonamido, phosphonyl, phosphinyl, phosphino,
phosphonium, keto, ester, carbamyl, ureido, thiocarbonyl, borate,
borane, boraza, silyl, siloxy and silaza radicals, and combinations
thereof; wherein X, Y and Z are pharmaceutically acceptable
counterions or together are a pharmaceutically acceptable
polydentate ligand, or are independently attached to one or more of
the R groups and n is an integer from 0 to 3.
[0049] Specific examples of the above general formula are provided
in the many examples below. While these specific examples provide
are provided, one of skill in the art will be able to determine
other variants within the scope of the above description. In
addition, one of skill in the art will be able to predict and
determine antianalgesic and antinociceptive effects of the other
variants using the teaching of the numerous examples below.
[0050] By an "analgesic amount" of the synthetic SOD catalysts
herein is meant an amount that significantly prevents or alleviates
pain in the human or lower animal being treated. At a certain level
stimuli are perceived as painful, while below that level they are
not. This level is referred to as the pain threshold. Healthy,
normal subjects exhibit a normal pain threshold that can be
quantified for a given stimulus. A normal healthy individual
perceives a pin prick as painful, but does not perceive the
movement of a joint within its normal range of motion as painful.
An individual suffering from arthritis has a lowered pain threshold
and will perceive such normal movement as painful. An individual
suffering from sunburn has a lowered pain threshold and may
perceive the touch of a finger to be as painful as a normal
individual perceives a pin prick. Because these compounds operate
to elevate a lowered pain threshold, they will be effective in the
treatment of such pain, and an "analgesic amount" of synthetic SOD
catalysts in the treatment methods provided here also means an
amount that significantly elevates the pain threshold above its
pre-treatment level or prevents the pain threshold from being
lowered by a pathological condition. From the standpoint of the
pharmacologist and pharmaceutical scientist, this can be measured
prospectively using common animal models such as the phenylquinone
writhing model, the rat tail flick (radiant heat) model, the
carrageenan inflammation model, the Freund's adjuvant model, and
other pain models well known to pharmacological science. From the
standpoint of the clinician, this can be measured according to the
subjective response of each patient to a unit dose of the compound,
and subsequent doses can be titrated to achieve the desired level
of analgesia within the therapeutic range of the compound
employed.
[0051] By an "amount sufficient to prevent or reverse tolerance to
opioids" is meant The dual administration of a superoxide dismutase
catalyst together with an opioid such as morphine or fentanyl
allows lower doses of the morphine or fentanyl to elicit its
analgesic effects while limiting its side effects. Moreover, a
superoxide dismutase catalyst can reverse opioid tolerance in
patients who have already developed tolerance. Thus, the superoxide
dismutase catalysts restore the analgesic effect lost during
prolonged treatment with an opioid. These catalysts prevent or
reverse the tolerance to opioids without many of the side effects
of other compounds proposed for this purpose, such as clonidine and
buprenorphine. And in contrast to other proposed compounds, such as
inhibitors of inducible nitric oxide synthase, the superoxide
dismutase catalysts themselves have potent analgesic effects that
are useful in hyperalgesic conditions such as burns, arthritis and
other inflammatory diseases, migraine, and pain associated with
tumor infiltration and cancer therapy.
[0052] The compounds of this invention are also useful as adjuncts
in the prevention and treatment of pain with opioid analgesics,
nitric oxide donors or nonsteroidal anti-inflammatory compounds. In
preferred embodiments, the superoxide dismutase catalyst is
administered conjointly with the opioid, NO.sub.2 donor or NSAID
compound. Administered in conjunction with an opioid, the
superoxide dismutase catalyst potentiates the opioid and prevents
development of tolerance and hyperalgesia. Administered after
opioid tolerance, hyperalgesia and/or dependency have developed,
the superoxide dismutase catalyst reverses the tolerance and
hyperalgesia and reduces the symptoms of the withdrawal syndrome.
Administered in conjunction with an NSAID compound or nitric oxide
donor, the superoxide dismutase catalyst potentiates both the
analgesia and the inflammatory action of the NSAID or NO.sub.2
donor. These drug moieties can also be linked to provide
bifunctional compounds of the formula A.sub.n-Q.sub.m, wherein A is
a superoxide dismutase catalyst moiety, Q is selected from
nonsteroidal anti-inflammatory drug moieties, nitric oxide donor
moieties and opioid analgesic drug moieties, and n and m are
independently integers from 1 to 3. Depending upon the selection of
A and Q, this can easily be done by substituting the NSAID or
opioid moiety for one or more of counterion/ligands X, Y and Z in
the preferred formula above. A simple approach to providing a
combination containing a nitric oxide donor is to attach one or
more nitrate or nitrite groups to the superoxide dismutase
compound.
[0053] While not intending to be limited by theory, it is believed
that the opioid withdrawal syndrome has many symptoms in common
with the withdrawal syndromes associated with other addictive
compounds and behaviors, including symptoms of withdrawal from
cocaine, nicotine, and eating disorders such as anorexia and
bulimia, especially the hyperreflexia and hyperalgesia associated
with withdrawal. Accordingly, this invention also provides a method
of preventing and treating symptoms of addition withdrawal, by
administering to a patient in need of such treatment an amount of a
superoxide dismutase catalyst that is safe and effective to prevent
or reduce such symptoms.
[0054] A safe and effective amount of the compounds used in the
practice of this invention is an amount that provides analgesia,
thereby alleviating or preventing the pain being treated at a
reasonable benefit/risk ratio as is intended with any medical
treatment. In using the compounds for the reversal of opioid
tolerance or reduction of withdrawal symptoms, these endpoints are
used rather than analgesia. Obviously, the amount of catalyst used
will vary with such factors as the particular condition that is
being treated, the severity of the condition, the duration of the
treatment, the physical condition of the patient, the nature of
concurrent therapy (if any), the route of administration, the
specific formulation and carrier employed, and the solubility and
concentration of catalyst therein.
[0055] By "systemic administration" is meant the introduction of
the catalyst or composition containing the catalyst into the
tissues of the body, other than by topical application. Systemic
administration thus includes, without limitation, oral and
parenteral administration.
[0056] Depending upon the particular route of administration, and
compatibility with the active compound chosen, a variety of
pharmaceutically-acceptable carriers, well-known in the art, may be
used. These include solid or liquid filler, diluents, hydrotropes,
excipients, surface-active agents, and encapsulating substances.
The amount of the carrier employed in conjunction with the catalyst
is sufficient to provide a practical quantity of material per unit
dose.
[0057] Pharmaceutically-acceptable carriers for systemic
administration that may be incorporated into the compositions of
this invention, include sugars, starches, cellulose and its
derivatives, malt, gelatin, talc, calcium sulfate, vegetable oil,
synthetic oils, polyols, alginic acid, phosphate buffer solutions,
emulsifiers, isotonic saline, and pyrogen-free water.
[0058] The catalysts can be administered parenterally in
combination with a pharmaceutically acceptable carrier such as corn
oil, Cremophor EL or sterile, pyrogen-free water and a
water-miscible solvent (e.g., ethyl alcohol) at a practical amount
of the catalyst per dose. Preferably, the
pharmaceutically-acceptable carrier, in compositions for parenteral
administration, comprises at least about 90% by weight of the total
composition. Parenteral administration can be by subcutaneous,
intradermal, intramuscular, intrathecal, intraarticular or
intravenous injection. The dosage by these modes of administration
is usually in the range of from about 0.1 mg to about 20 mg per
day.
[0059] Various oral dosage forms can be used, including such solid
forms as tablets, capsules, granules and bulk powders. These oral
forms comprise a safe and effective amount, usually at least about
5%, and preferably from about 25% to about 50% of the catalyst.
Tablets can be compressed, tablet triturates, enteric-coated,
sugar-coated, film-coated or multiple compressed, containing
suitable binders, lubricants, diluents, disintegrating agents,
coloring agents, flavoring agents, preservatives, flow-inducing
agents, and melting agents. Liquid oral dosage forms include
aqueous solutions, emulsions, suspensions, solutions and/or
suspensions reconstituted from noneffervescent granules and
effervescent preparations reconstituted from effervescent granules,
containing suitable solvents, preservatives, emulsifying agents,
suspending agents, diluents, sweeteners, melting agents, coloring
agents, and flavoring agents. Preferred carriers for oral
administration include gelatin, propylene glycol, ethyl oleate,
cottonseed oil and sesame oil. Specific examples of
pharmaceutically-acceptable carriers and excipients that may be
used to formulate oral dosage forms containing the catalysts used
in this invention, are described in U.S. Pat. No. 3,903,297,
Robert, issued Sep. 2, 1975, incorporated by reference herein.
Techniques and compositions for making solid oral dosage forms are
described in Marshall, "Solid Oral Dosage Forms," Modern
Pharmaceutics, Vol. 7 (Banker and Rhodes, editors), 359-427 (1979),
incorporated by reference herein.
[0060] By "pharmaceutically acceptable salts" is meant those salts
that are safe for topical or systemic administration. These salts
include the sodium, potassium, calcium, magnesium, and ammonium
salts.
EXAMPLES
[0061] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The following specific
examples are offered by way of illustration and not by way of
limiting the remaining disclosure. Where Sprague-Dawley rats are
mentioned below, 175-200g Sprague-Dawley rats were used (Harlan
Sprague Dawley, Indianapolis, Ind., USA) and housed and cared for
under the guidelines of the Institutional Animal Care and Use
Committee. They received a subplantar injection of carrageenan (0.1
mL of a 1% suspension in 0.85% saline) into the right hind paw. At
three hours post-carrageenan, when hyperalgesia is normally at a
maximum, the test compound was administered intravenously at
dosages of from 1-6 mg/kg. Hyperalgesia is assessed at thirty
minutes to three hours post-administration of test compound.
Example 1
SODm Effect on Carrageenan Paw Hyperalgesia
[0062] SOD catalyst compounds were evaluated in the carrageenan
hyperalgesia model described above. Results were as follows:
1 Compound Result SC-71354 No effect at tested dosages by
intravenous injection* SC-69604 No effect at tested dosages by
intravenous injection SC-71449 No effect at tested dosages by
intravenous injection SC-72325 Inhibited hyperalgesia 64% at 30
minutes SC-73770 Inhibited hyperalgesia 72% at 30 minutes *Higher
dosage levels and other routes of administration were not tested
for any of the compounds.
Example 2
Reducing Hyperalgesia Using SODm
[0063] Analgesia provided by intravenous SC-72325 was evaluated
over time in the carrageenan model. Results are shown in FIG.
1.
Example 3
Comparison of Carrageenan Paw Hyperalgesia Treatments
[0064] Analgesia provided by intramuscular injection of SC-72325
was evaluated over time in the carrageenan model in comparison to
the anti-inflammatory drug ketorolac. Results are shown in FIGS. 2
and 3, respectively.
Example 4
Baseline for Carrageenan Paw Hyperalgesia Testing
[0065] To determine whether the SOD catalyst compounds provide
analgesia by some action on the prostaglandin-leukotriene system,
release of prostaglandin PGE-2 was measured in rat paw exudate from
the carrageenan model as well as in spinal cord fluid. Saline was
used as a non-inflamed control and the anti-inflammatory ketorolac
was used as a positive anti-inflammatory control. Results are shown
in FIGS. 4 and 5. SC-72325 did not significantly reduce release of
PGE-2 compared to the carrageenan-injected but untreated rats.
Ketorolac treated rats had levels of PGE-2 release similar to
non-carrageenan injected animals.
Example 5
Morphine Tolerance Testing
[0066] Mice were treated twice a day with either saline (naive) or
morphine (s.c., 10 mg/kg) for a period of 4 days to induce
tolerance. For comparison, a dose of 10 mg, or less than 0.15 mg/kg
every 4 to 10 hours, is a morphine dosage routinely prescribed for
the 70 kg. human adult with severe pain. On day 5, all mice
received a subcutaneous challenge dose of 3 mg./kg morphine and the
level of analgesia was measured 30 minutes later. Results are shown
graphically in FIG. 6. Dose response measurements in normal mice
have indicated that a challenge dose of 3 mg/kg would elicit 90%
analgesia in naive or non-tolerant mice when assessed by the
standard hot plate test. In this example, mice that were treated
with morphine for 4 days showed a decreased analgesic effect from
morphine on day 5 when compared with the naive mice. Tolerance to
morphine was eliminated in mice that were treated with the
superoxide dismutase catalyst SC-72325 administered
intraperitoneally.
Examples 6-167
[0067] The following compounds were made for use as superoxide
dismutase catalysts or as ligands for combination with transition
metal ions for use as superoxide dismutase catalysts within the
scope of the invention. The catalytic rate constant k.sub.cat is
given for each compound. For k.sub.cat values marked with an
asterisk, the k.sub.cat was measured at a pH of 8.1. For all other
compounds the k.sub.cat was measured at pH 7.4. Compounds marked NT
were made but not tested. The ligands of Examples 11, 101, 123-135
and 138-148 were not expected to have activity without the metal
ion and most were not tested. However, as can be seen by comparison
of Examples 148 and 149, insertion of the metal ion into the ligand
forms a complex with good superoxide dismutase activity.
6789101112131415161718192021222324
[0068] In Examples 168-171 below, male Sprague-Dawley rats were
used and all drugs were dissolved in 26 mM NaHCO.sub.3 buffer
(0.218 g NaHCO.sub.3 in 100 ml dH2O; pH=8.1 to 8.3) and injections
were given subcutaneously (hereinafter "s.c."). When drug
combinations were employed, each drug was injected separately, but
concurrently. Drugs employed morphine sulfate and SC-72325A,
Example 167 which is an enantiomer of SC-72325 also depicted above.
In some studies ketorolac was also used and was given by s.c.
injection.
[0069] Thermal hyperalgesia and antinociception were assessed in
the testing of SC-72325A for treatment of pain. Thermal
hyperalgesia was determined by the method of Hargreaves et al.,
Pain, 32:77-88 (1988). A radiant heat source was focused onto the
plantar surface of the affected paw of nerve-injured or
carageenan-injected rats. When the animal withdrew its paw, a
motion sensor halted the stimulus and timer. A maximal cut-off of
40 seconds was utilized to prevent tissue damage. Paw withdrawal
latencies were thus determined to the nearest 0.1 seconds. Reversal
of thermal hyperalgesia was indicated by a return of the paw
withdrawal latencies to the pre-tremeant baseline latencies (i.e.,
21 seconds). Antinociception was indicated by a significant
(p.ltoreq.0.05) increase in paw withdrawal latency above this
baseline. Data were converted to % antihyperalgesia or %
antinociception by the formula:
100.times.(test latency--baseline)/(cut-off baseline)
[0070] where cut-off was 21 seconds for determining
antihyperalgesia and 40 seconds for determining
antinociception.
[0071] Dose response curves were generated for each drug and drug
combination for data obtained at the time of peak effect, which was
consistently at the 30 minute time point.
[0072] Studies employing combinations of drugs were analyzed for
additive or synergistic interactions by isobolographic analysis as
described by Tallarida (Tallarida et al., Life Sciences, 45:947-61,
1987) and employed by other (Ossipov et al., J. Pharmacol. Exp.
Ther., 255:1107-1116, 1990; Porreca et al., Euro. J. Pharm., 179:
463-468, 1990) by means of a customized Visual Basic computer
program (Ossipov, personal communication). Log dose-response curves
for each component administered alone were established and the
A.sub.50 (95% C.L.) were calculated.
[0073] Using these methods, the amount of synergy of a combination
of compositions can be determined. The preferred combinations of
the present invention treat pain using a smaller dose of an
analgesic, such as an NSAID or opioid, when compared to
administering the analgesic alone. In other words, a preferred
combination will result, for example, in the same amount of pain
relief after administering 50 mg of an NSAID or opioid in
combination with 50 mg of a synthetic superoxide dismutase catalyst
as would normally result from administering 500 mg of an NSAID or
opioid alone or 500 mg of a synthetic superoxide dismutase catalyst
alone.
[0074] Conversely, the preferred combinations of the present
invention treat pain to a greater extent when compared to treating
pain with an analgesic alone or a synthetic superoxide dismutase
catalyst alone. In other words, a preferred combination will
result, for example, in an equivalent amount of pain relief after
administering 500 mg of an NSAID or opioid in combination with 50
mg of a synthetic superoxide dismutase catalyst as would normally
result from administering 1,000 mg of the NSAID or opioid or 1,000
mg of a synthetic superoxide dismutase catalyst alone.
[0075] Thus, preferred combinations result in additive or
synergistic antihypertensive or antinociceptive effects allowing an
NSAID or opioid to be administered in a dosage that is at least 50%
less than the same NSAID or opioid administered alone. More
preferably, the NSAID or opioid combination may be administered in
a dosage that is at least 25% less than the same NSAID or opioid
administered alone to achieve said therapeutic effect. Still more
preferably, the NSAID or opioid may be administered in a dosage
that is at least 10% less than the same NSAID or opioid
administered alone to achieve said therapeutic effect. And still
more preferably, the NSAID or opioid may be administered in a
dosage that is at least 1% less than the same NSAID or opioid
administered alone to achieve said therapeutic effect.
[0076] The A.sub.50 for the log dose-response curve of a drug
mixture at a fixed ratio was calculated in terms of "total dose"
administered. For a given drug combination a theoretical A.sub.50
exists such that A.sub.50 add=A.sub.50
drug1.times.(p.sub.1+Rp.sub.2) where R is the potency ratio of drug
1 to drug 2, p.sub.1 is the proportion of drug 1 in the mixture and
p.sub.2 is the proportion of drug 2. Variances and 95% C.L. for the
theoretical additive A.sub.50 are derived from the variances of
each drug administered alone. A t-test is employed to compare the
theoretical additive A.sub.50 and 95% C.L. to that obtained for the
mixture. A significantly ((p <0.05); t-test) lower experimental
value compared to theoretical value denotes a synergistic
interaction. See Table 1 below.
Example 168
SC-72325A Treats Pain
[0077] Analgesic effects provided by subcutaneous injection of
SC-72325A was studied by formalin-induced hind paw licking
response. Male CD-1 mice (Charles River, 28-35 gm) were allowed to
feed ad libitum. Mice were housed 5-7 per cage in a temperature
controlled room with a twelve hour light-dark cycle. Determination
of antinociception was assessed between 7:00 and 10:00 AM. Groups
consisted of 7-14 mice, and each animal was used for one
experimental condition. The antinociceptive effects of SC-72325A
were tested in the formalin-induced hind paw licking procedure
(Hunskaar et al., Pain, 30: 103-114, 1987). Mice were injected with
by sub-plantar administration with formalin (20 .mu.g of a 1% stock
solution) and the duration of paw licking was monitored in the
periods of 5-10 minutes (Phase I) and 15-30 minutes (Phase II)
thereafter. SC-72325A (10 mg/kg) was given s.c. 10 minutes prior to
formalin.
[0078] At 10 mg/kg, the s.c. injection of SC-72325A had a small
inhibitory effect on phase 1 of the response but nearly completely
abolished Phase II of the response. See FIG. 6.
Example 169
Antihyperalgesia and Antinociception Synergy Using SC-72325A and
Morphine Combination
[0079] Carrageenan-induced inflammation is a well characterized and
commonly employed model of peripheral inflammation. This procedure
reliably produces a marked inflammatory response within 3 hours of
injection which is indicated by swelling of the hind paw, edema,
rubor and hyperalgesia and allodynia (Kocher et al., 1987, Ossipov
et al., 1995). Peripheral inflammation was induced in the hind paw
of male Sprague-Dawley rats by injecting 0.1 ml of a 2%
.lambda.-carrageenan suspension into the subplanar surface of the
hind paw of lightly ether-anesthetized rats. All drugs were
prepared according to the methods set forth in Example 6, above.
Testing was performed 15, 30, 45, 60, 120 and 180 minutes after
drug injections. The s.c. injection of SC-72325A produced
time-related and dose-dependant antihyperalgesia over the dose
range of 0.3 to 30 mg/kg. See FIG. 7. Similarly, morphine also
produced time-related and dose-dependent antihyperalgesia and
antinociception over the dose range of 0.03 to 10 mg/kg. The 1:1
combination of SC-72325A with morphine produced antihyperalgesia
activities at much lower doses than either drug alone. See FIG. 8.
Isobolographic analyses revealed that the combination of SC-72325A
with morphine resulted in a definitive synergistic interaction
against hyperalgesia; the A.sub.50 values with confidence intervals
are presented in Table 1, below. The antihyperalgesic A.sub.50
value for the 1:1 combination of SC-72325A plus morphine was 0.046
mg/kg, s.c., which was significantly (p.ltoreq.0.05) less than the
calculated theoretical A.sub.50 value for the combination if the
activity was additive. See Table 1. SC-72325A also exhibited a
slight antinociceptive effect.
2 TABLE 1 Antihyperalgesia A.sub.50 (mg/kg, s.c.) SC-72325A 1.34
Morphine 0.22 Morphine + SC-72325A 0.046 Theoretical Additive Curve
0.380
[0080] FIG. 9 shows that the onset of action SC-72325A was much
faster than the one obtained with ketorolac. In fact, when compared
to ketorolac, SC-72325A was more potent and more efficacious in
this model.
Example 170
SC-72325A Inhibition of Neuropathic Pain
[0081] Neuropathic pain (L.sub.5/L.sub.6 SNL) was also utilized to
assess the antinociceptive effects of SC-72325A. Nerve ligation
injury was performed according to the method described by Kim and
Chung (1992). This technique reliably produces signs of clinical
neuropathic dysesthesias, including tactile allodynia, thermal
hyperalgesia and behavior suggestive of spontaneous pain. Rats were
anesthetized with 2% halothane in O.sub.2 delivered at 2
liters/minute. The skin over the caudal lumber region was incised
and the muscles retracted. The L.sub.5 and L.sub.6 spinal nerves
were exposed, carefully isolated, and tightly ligated with 4-0 silk
suture to the dorsal root ganglion. After ensuring homeostatic
stability, the wounds were sutured, and the animals allowed to
recover in individual cages. Any rats exhibiting signs of motor
deficiencies were euthanized. Testing was performed 15, 30, 45, 60
and 90 minutes after drug injections.
[0082] The s.c. injection of SC-72325A produced time-related and
dose-dependent antihyperalgesia over the dose range of 1 to 30
mg/kg. See FIG. 10. One of the highest doses tested, 10 mg/kg,
produced an antihyperalgesic effect of 91.+-.8.8% MPE and an
antinociceptive effect of 39 .+-.6.4% MPE 30 minutes after
injection. SC-72325A also exhibited a slight antinociceptive
effect.
Example 171
SC-72325A Inhibition of Allodynia
[0083] Chronic constriction injury was performed as described by
Bennett and Xie (1988). Male Sprague-Dawley rats were lightly
anesthetized and the sciatic nerve isolated and exposed. Four
chronic gut ligatures (4-0) are loosely placed around the nerve
about 1 to 2 mm apart and the wound closed. Signs of hyperalgesia
and spontaneous pain, including guarding of the hind paw and
spontaneous nocifensive responses are normally present within 4
days of surgery. Any rats exhibiting signs of motor deficiency were
euthanized. Cold allodynia was evaluated by placing rats in a
shallow pan of ice water (0.degree. C., 3 cm deep). The response
latency to withdrawal of the hind paw or escape behavior is
measured. Normal or sham-operated rats typically show no response
during the 30 second exposure to the ice water. Testing was
performed 15, 30, 45 and 60 minutes after drug injections. Drugs
were given by s.c. injection.
[0084] The s.c. injection of SC-72325A produced time-related and
dose-dependent attenuation of cold allodynia over the dose range of
1 to 10 mg/kg. See FIG. 11.
[0085] Other Embodiments
[0086] The detailed description set-forth above is provided to aid
those skilled in the art in practicing the present invention.
However, the invention described and claimed herein is not to be
limited in scope by the specific embodiments herein disclosed
herein because these embodiments are intended as illustration of
several aspects of the invention. Any equivalent embodiments are
intended to be within the scope of this invention. Indeed, various
modifications of the invention in addition to those shown and
described herein will become apparent to those skilled in the art
from the foregoing description which do not depart from the spirit
or scope of the present inventive discovery. Such modifications are
also intended to fall within the scope of the appended claims.
[0087] References Cited
[0088] All publications, patents, patent applications and other
references cited in this application are incorporated herein by
reference in their entirety for all purposes to the same extent as
if each individual publication, patent, patent application or other
reference was specifically and individually indicated to be
incorporated by reference in its entirety for all purposes.
Citation of a reference herein shall not be construed as an
admission that such is prior art to the present invention.
* * * * *